The role of glycemic control in the pathogenesis of diabetic nephropathy has been clearly established. Nonetheless, glycemic control does not explain why only 30%-40% of diabetic individuals are at risk for late and irreversible stages of diabetic renal disease. Familial clustering of diabetic nephropathy in both type 1 and type 2 diabetes suggests that genetic susceptibility may answer this puzzle. The relative risk for a diabetic sibling of a patient with diabetic nephropathy has been estimated at between 3.5 and 10, with higher risk estimates in families of Africa-American background. We propose that diabetic nephropathy results from the expression of a common, major susceptibility allele that in interaction with several secondary loci is expressed in the hyperglycemic milieu.